Multiple Sclerosis and Affective Disorders* E. JANE GARLAND,
M.D. 1 AND
AP.
ZIS, M.D. 2
psychotic reactions remains speculative, the occurrence of a mood disturbance as a complication of anti-inflammatory therapy is so frequent that prophylactic lithium therapy has been recommended for MS patients receiving ACTH (8). The widely used diagnostic classification system, DSM-III-R (9), specifies that major affective disorders and organic affective disorder are mutually exclusive diagnoses. The diagnosis of organic affective disorder would lead to the treatment of the underlying organic cause as the primary treatment of affective symptoms. On the other hand, the diagnosis of acute affective symptoms of a functional nature might lead to deliberate avoidance of specific anti-inflammatory agents which may precipitate psychiatric symptoms. This dilemma has received little attention in the psychiatric literature. Authors discussing affective symptoms in the presence of MS have tended to favour either an organic or functional causation. Yet the clinician is frequently confronted with complex multifactorial causation and with the problem of recommending optimal treatment. The purpose of this report is to review the evidence of an association between MS and depressive symptoms, major depressive disorder and bipolar disorder with a particular emphasis on the various factors which may account for this association. Two case reports are included to illustrate the complex interplay of biological and psychosocial factors in the genesis of major affective disorders in patients with MS.
Affective disorders occurring in association with multiple sclerosis have been attributed both to the psychosocial impact of a chronic disabling illness and to the structural lesions of cerebral demyelination. A review of research evidence suggests that while there is a correlation between chronic depressive symptoms and both progressive disability and lack of social support, acute major depressive and manic episodes may be psychiatric manifestations of demyelinating lesions and may be the initial presenting symptoms of multiple sclerosis. Anti-inflammatory agents may be required in the management of acute psychiatric symptoms despite the fact that these agents have a propensity to precipitate psychotic episodes. Two case reports are presented to illustrate the clinical challenge of distinguishing between organic and functional affective illness in patients with multiple sclerosis. The interplay between biological and psychological aspects of multiple sclerosis in precipitating affective disorders is discussed, with implications for patient assessment and management.
C
hanges in prevailing mood and emotional control have been recognized as being characteristic of multiple sclerosis (MS) since the publication of landmark reports earlier this century (1,2). However, the association between MS and specific mood disorders, including major depressive episodes (3) and bipolar affective disorder (4), has only recently been documented. There are several hypothetical explanations for this observed association. First, MS could act as a psychological stressor precipitating depression or mania in a psychologically and/or biologically predisposed individual. Second, MS produces specific structural lesions which may cause affective disorders. Third, susceptibilities to MS and to affective disorders may be genetically linked. A confounding factor in this field is the fact that drugs used in the treatment of MS are known to produce mood changes. Corticotrophin (ACTH) and corticosteroids may precipitate manic or depressive psychotic episodes in patients treated for inflammatory disorders (5-7). While the mechanism of these
Depression and Multiple Sclerosis When examining the relationship between depression and MS, it is important to distinguish between depressed mood and major depressive episodes. Systematic documentation of the occurrence of major depressive episodes has occurred only in recent surveys. Earlier reports of depressive symptomatology are summarized in Table I. Notable in the earliest studies of clinical populations (1,2) are the frequent reports of affective instability (86% to 97%) suggestive of organic disinhibition, compared with the low rates of self-reported depressive symptoms (ten percent to 17.5%). Subsequent studies have documented more selfreported depressive symptoms in patients with MS than in neurological controls (10) or healthy controls (II). This relationship holds even when depression inventory items potentially reflecting MS symptoms are eliminated (II). Several studies indicate that there is a correlation between depressive symptoms in MS patients and both progressive disability and lack of social support, and that they are no more frequent than in neurological controls with non cerebral disorders matched for disability (11-15). It has been concluded,
*Manuscript received August 1989; revised December 1989. I Clinical Instructor, Department of Psychiatry, University of British Columbia, University Hospital- UBC Site.Vancouver, British Columbia. 2Professor, Department of Psychiatry.University of British Columbia. University Hospital- UBC Site, Vancouver. British Columbia. Address reprints requests to: EJ. Garland. M.D .• 2211 Wesbrook Mall. Vancouver BC V6T 2B5
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Table I Surveys of Depressive Symptoms in Patients with Multiple Sclerosis N
Controls
DepressiveSymptoms
Comments
Cottrell (I)
100
10% pessimistic
97% loss·of emotional control
Sugar (2)
28
17.5%dysphoric
86% loss of emotional control
Pratt (10)
100
100
29% "cry easily" versus 17%of controls
significantdifference; neurological controls
Baldwin (II)
85
85
MMPI: significantincrease in depression hypochondriasis and hysteria scales in MS
healthy controls; scale items reflecting MS symptoms eliminated
Surridge (12)
100
39
27% of MS patients depressed in psychiatricinterviewversus 13%of controls (not statistically significant)
matchedfor disability
McIvor (13)
120
Beck Depression Inventory scores elevated
correlationbetween symptoms and disability and lack of support
therefore, that these depressive symptoms are "reactive". However, Rabins et al (16) reported that depression scores were higher in MS patients with more clinically diagnosed brain involvement, suggesting a role for "organic" factors. Studies of major depressive episodes in MS patients are summarized in Table II. These studies were preceded by several case reports (17,18). Gallinek and Kalinowsky (17) reported three cases which were judged to be "reactive" in nature, including two cases that responded to ECT. Goodstein and Ferrell (18) reported three cases in which single or multiple depressive episodes preceding neurological symptoms were viewed in retrospect as the first manifestations of MS. It is notable, however, that the neurological symptoms had been initially viewed as "psychogenic" in these cases. Whitlock and Siskind (3), in the first systematic study of depressive episodes in MS patients, found a higher incidence of major depressive episodes in MS patients after the onset of MS than in neurological controls matched for disability. In two patients, depressive episodes occurring prior to MS diagnosis were believed to represent demyelinat-
ing episodes. Scores on the Beck Depression Inventory (BDI) were higher in MS patients, especially those whose disability was more severe. Whitlock and Siskind's data support Goodstein and Ferrell's hypothesis that there is a true association between major affective disorders and MS; MS lesions cause symptoms rather than precipitating major depressive episodes through psychological mechanisms. Consistent with earlier surveys (11-14), however, this report also suggests that progressive disability may predispose patients with MS to developing chronic depressive symptoms. While family histories of affective disorder were not reported, it was noted that MS patients did not receive more drugs that are likely to produce depressive symptoms than did controls. Schiffer (19) examined the role of structural lesions in producing depressive symptoms by comparing cerebral MS with noncerebral MS patients matched on the Kurtzke Disability Scale, finding a higher incidence of major depressive episodes in patients with cerebral MS. These results suggest that structural damage is involved in the genesis of major depression. The observation that a similar degree of cognitive
Table II Reports of Major Depressive Episodes in Patients with Multiple Sclerosis Subjects
Incidenceof Major Depression
Whitlock (3)
30 with MS; 30 neurologicalcontrols matched for disability
16of the MS cases; 5 of the controls
significantdifference; BOI scores higher in MS cases; MS onset with depression in 2 cases
Schiffer (4)
15 with cerebral MS; 15 with noncerebral MS
9 of the cerebral MS cases; 2 of the non cerebral MS cases
significantdifference; matched for disability; BOI scores not different
Joffe (20)
100consecutive patients at an MS clinic
55 met the SADS-Lcriteria for major affective disorder: 42 with major depression; 13 with bipolar affective disorder
family incidenceof affective disorder not elevated
Comments
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CANADIAN JOURNAL OF PSYCHIATRY
impairment occurred in both groups suggests that the depressive symptoms were the result of specific lesions rather than reflecting a generalized decrease in cognitive functioning, which might impair coping strategies. The question of whether or not susceptibilities to MS and to depressive disorder are genetically linked has received little attention in these reports. However, Joffe et al (20) recently reported a 42% lifetime occurrence of major depressive episodes in MS clinic patients. The incidence of family histories of affective illness was not higher than in the general population, data which argue strongly against this hypothesis. Response to specific treatment may provide circumstantial evidence of a particular etiological factor. Schiffer (21) has recently reported the results of a management protocol in which 20 MS patients with a major depressive episode were assigned to medical, psychological or social treatment according to the presumed major etiological precipitant. Regardless of treatment strategy, depressive episodes were resolved within five weeks in 12 of the 13 patients with relapsing or progressive MS. In contrast, seven of eight patients who developed depressive episodes during remission remained depressed regardless of treatment. These results could be consistent with the etiological role of either organic or psychosocial factors. The available evidence to date suggests that there is a con-elation between the presence of depressive symptoms in MS patients and disability and lack of social support, which may not be unique to MS, while major depressive episodes may be the result of the structural lesions of MS. Factors limiting the interpretation of these data include the well known impact of symptoms of medical illness on depression scales (22), the lack of information on genetic predisposition to developing an affective disorder in some study populations, and the lack of data on the localization of MS structural lesions which might provide a pattern correlating with affective illness (23). The availability of magnetic resonance imaging (MRI) to assist in localizing MS lesions may enhance our understanding of this field. Arecent MRI study of patients suffering from MS found a greater degree of temporal lobe involvement in eight MS patients with psychiatric disorders than in MS controls matched for age, sex, duration, severity and course of illness (24). Bipolar Affective Disorders and Multiple Sclerosis Early investigators of psychological changes in MS reported a high incidence of euphoria and "eutonia", or abnormal sense of bodily well-being. Euphoria was noted in 63% of Cottrell and Wilson's study population (1) and 54% of Sugar and Nadell's (2). While these early reports suggested a low incidence of intellectual deterioration, Surridge (12) demonstrated intellectual deficits in 60%, hyponosognosia in 31 %, and a relationship between cognitive impairment and euphoria, which has been confirmed in a recent report (14). Abnormal mood elevation may also be associated with concealed depression (13,14). However, hypomanic episodes were not noted in these reports. In a landmark paper review-
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ing the concept of organically caused "secondary mania" (25), mention of MS as a cause is conspicuously absent. In a recent epidemiological study, Schiffer (4) demonstrated a greater than expected statistical association between bipolar affective disorder and MS in Monroe County, USA. In the ten cases identified, the affective disorder began after the onset of the neurological symptoms. A family history of affective illness was present in half of these cases. Joffe et al (20) subsequently reported a lifetime occurrence of bipolar disorder in 13 of 100 consecutive MS clinic patients. There was no difference between the incidence of a family history of affective disorder in MS patients and that in the general population. While a true association is suggested and there is no evidence to support genetic linkage, the data provided do not indicate whether MS was a psychological stressor or a direct organic cause, or whether affective illness occurred during treatment of MS with agents known to cause psychiatric symptoms. . Table III summarizes case reports of mania and cyclical mood disturbances in association with MS. Although these are anecdotal, several important observations appear in these reports: acute mania may be a clinical presentation of MS (26-29); neurological signs of MS may be misdiagnosed as lithium or neuroleptic toxicity (27,28) or "dismissed" as psychogenic (30); and treatment of manic symptoms in these patients may require anti-inflammatory agents (27,29). All of these authors have suggested that the mood disorder is a manifestation of the demyelinating disorder. While in some cases the mood disorder is a clinical manifestation of acute demyelination, in other reported cases the structural damage of MS plaques is reflected in a chronic, treatment-resistant cyclical mood disturbance (30). Bipolar mood disorder occurs in association with multiple sclerosis at a rate greater than that predicted by chance and in the absence of a predisposing family history. This appears to be an organic mood disorder. Case Reports Case 1 A 32 year old married professional woman with two young children presented with a major depressive episode with mood congruent and incongruent psychotic features. The symptoms had developed insidiously during the six months after the acute onset of multiple sclerosis. The diagnosis of MS had been confirmed by compterized tomography (CT) scan, magnetic resonance imaging (MRI), and cerebrospinal fluid changes. Since her initial presentation with diploplia, dysarthria, left-sided weakness and paresthesia after a flu-like illness, she had experienced several exacerbations of neurological symptoms and was unable to return to work. She reported progressive fatigue, social withdrawal, depressed mood, apathy, anhedonia, indecisiveness and ruminations of guilt. She developed initial insomnia and early morning wakening, anorexia with a 5 kg weight loss and passive suicidal ideation. She had paranoid delusions that her husband was planning to divorce her and that she was being covertly observed by detectives, family members and
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Table III Case Reports of Bipolar Affective Disorder and Multiple Sclerosis Age
Case
Sex
Order of Symptom Presentation
Comments
Cremieux (26)
'47
M
mania followed by neurological symptoms5 monthslater; cyclical manic depressiveillnessand progressive neurological symptoms, fatal 2 years later
autopsy findings includedtemporal lobe, thalamic and periventricular lesions
Peselow(27)
29
M
neurological symptoms simultaneously with mania which was unremitting for 8 months
neurological symptoms initiallymisdiagnosed as neuroleptic and lithium toxicity; mania unremitting until prednisonetherapy instituted
Solomon (28)
58
M
mania followed 6 months later by neurological symptoms
neurological symptoms misdiagnosed as lithium toxicity
Mapelli (29)
26
F
transientneurological symptomsfollowed 3 years laterby mania; neurological symptomssimultaneous with second manic episode
second manic episode required treatment with ACTH and neuroleptics
Kellner (30)
29
F
rapid cycling mood disorderfor 3 years followed by neurolgical symptoms
history of "conversionreaction" 4 years prior to onset of mood disorder
Kellner (30)
53
F
rapid cycling mood disorder for 3 years followed by neurological symptoms
neurological symptomsmisdiagnosed as alcoholic'cerebellar ataxia
therapists. She reported hallucinatory voices commenting on her behaviour and mocking her for her failures. There were also several episodes of formed visual hallucinations of animals. On psychiatric admission, the patient presented with marked psychomotor retardation, profoundly depressed mood, flattened affect, delusions of a paranoid type, and hallucinatory voices making derogatory comments. Physical examination revealed a resting tremor in the left leg, bilateral optic atrophy, hyperreflexia and left extensor plantar response. While she had no prior history of psychiatric illness, her personal history suggested a biological and psychological predisposition to depression. The patient's mother had received ECT for two major depressive episodes. As a child, the patient was introverted and isolated. Her father deserted the family when she was four. Her first serious relationship was with her husband and was characterized by insecurity, which she attributed to this early loss. Precipitating factors for depression occurred in the several years prior to the onset of MS. After years of marriage, she became pregnant. Ambivalent about both parenthood and abortion, her husband left the decision to her. She then felt guilty and anxious when the birth of twins severely strained the marriage. The onset of MS left her with a sense of personal, occupational and marital failure. Furthermore, because she believed in the metaphysical causation of illness, she blamed herself for unconsciously creating the illness to escape her many responsibilities.
Neurological assessment on her psychiatric admission did not reveal clinical evidence of acute demyelination. The daily administration of nortriptyline 75 mg and haloperidol 6 mg resolved her depression and delusions within four weeks. Individual and marital supportive psychotherapy was directed at helping the patient and her husband grieve appropriately for her diagnosis of MS, which they had not yet accepted. After resolution of the major depressive episode, clinical assessment suggested cognitive deficits manifesting as concrete thinking and problem solving inconsistent with the patient's educational level. Neuropsychological testing confirmed impaired problem solving, vulnerability to distraction, ideomotor apraxia and a 3 I point verbal-performance spread on the WAIS-R. A schizotypal personality pattern appeared on the MCMI. Repeat MRI scanning revealed new lesions since the examination three months previously. This suggests, in retrospect, that neurologically silent lesions may have contributed to the psychiatric disorder. Although the preferred diagnosis was a functional major depressive episode with psychotic features, clearly organic affective disorder could not be excluded.
ease 2 The patient was a 30 year old unemployed labourer who presented with acute mania and neurological deterioration followed by a depressive episode six months later. Seven years previously, the patient developed spontaneously resolving paresthesia of the left arm. When symptoms recurred two years later, multiple sclerosis was
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diagnosed, and the illness foIlowed a chronic relapsing and remitting course. During one episode several grand mal seizures occurred, and prednisone was administered without reported adverse effects. The first psychiatric admission was for acute mania accompanied by new symptoms of ataxia, dysarthria and paresthesia. There was a one week history of sleeplessness, overactivity, overspending, overtalkativeness with flight of ideas, grandiose delusions and extreme irritability. Because of the temporal association with neurological deterioration and the findings of new bifrontallesions using MRI, a diagnosis of organic affective disorder was made. The patient was treated with chlorpromazine and plasmapheresis followed by a cyclophosphamide trial, and his symptoms were resolved over several weeks. A history of depressive symptoms occurring three months previously was elicited at that time. Six months later the patient was readmitted with suicidal ideation. There was a six week history of depressed mood, insomnia with early waking, anorexia, decreased libido, poor concentration, apathy, anhedonia and ruminations of guilt that his illness was a punishment for his past antisocial behaviour. Three weeks prior to this admission, the neurologist had prescribed prednisone 60 mg daily because of increasing ataxia. The patient reported that his mood disturbance worsened after this was initiated, although his neurological symptoms improved. A mental status examination revealed depressed mood and affect, psychomotor retardation, ruminations of guilt, suicidal ideation, impaired concentration and markedly concrete interpretation of proverbs. Physical examination demonstrated ataxia, bilateral hyperreflexia, extensor plantar responses, dysdiadochokinesia and intention tremor on the left side. MRI scanning demonstrated numerous cerebral and cerebellar lesions including a prominent right temporal lobe lesion, but there were no new findings with the exception of progressive ventricular dilatation. The neurological assessment revealed that there was no evidence of active demyelination, and prednisone was tapered as planned. Imipramine was initiated at a dose of 50 mg daily. Within a week, the patient's mood, energy, concentration and psychomotor activity had dramatically recovered. He had no suicidal ideation and had realistic plans to enter a retraining program. He chose to discontinue imipramine therapy on discharge, and it was considered unlikely that this brief low dose antidepressant treatment had contributed substantially to his improvement. The working diagnosis at this point was organic bipolar affective disorder. Prednisone therapy was presumed to have contributed to depressive symptoms. It was noted that the patient's personal history suggested a biological, psychological and social predisposition to affective illness. There was a history of depression, alcohol abuse and violent suicide in his father and paternal uncle, and "mood swings" in a brother. The father left the family when the patient was seven years old and committed suicide when the patient was 14. The fifth of ten siblings, the patient had
Vol. 36, No.2
avoidant traits and developed antisocial behaviour patterns beginning in the year after his father's death, including minor criminal offenses, alcohol and recreational drug abuse. After failing to complete high school despite apparent ability, he drifted across the country working at odd jobs. He had repeated difficulty with employers and became estranged from his family. After his MS symptoms appeared, he was less able to perform physical labour, and employment became irregular. He became socially isolated and increasingly dependent on his live-in girlfriend for physical and financial support. He expressed chronic feelings of discouragement, self-blame and low self-esteem, which he continued to experience after his major depressive episode had been resolved. Discussion . The two cases presented demonstrate the complex interplay between biological and psychosocial factors in the genesis of affective illness in association with multiple sclerosis. These patients were genetically predisposed to affective disorders, and psychological predisposition was evident in both developmental histories. In each case there was an early loss of a parent and evidence of the psychological impact of this loss. For both of these patients, MS became one of a number of stressors which could precipitate an affective illness. Furthermore, there was evidence in each case to suggest that the structural lesions of MS contributed to the psychiatric illness. Recognition of the complex pathogenesis of affective illness in association with MS has several important practical implications. First, an acute affective disorder in a patient with MS should lead to careful neurological assessment to determine whether or not this could be a manifestation of acute demyelination. Computerized tomography or magnetic resonance imaging may be required to detect neurologically silent but psychiatrically manifested demyelination. Anti-inflammatory agents may therefore be specifically indicated in the presence of acute psychiatric symptoms, but coverage with lithium, neuroleptics or antidepressants is suggested. Second, even in a patient with an organic affective syndrome, psychodynamic and psychosocial factors need to be ascertained and addressed in order to reduce chronic depressive symptoms of a reactive nature. It can also be predicted that the individual with a structural lesion producing acute affective symptoms may be more prone to future episodes of an affective disorder, to which psychological stressors may contribute. Finally, the occurrence of transient, unexplained neurological disturbances in a patient with bipolar affective disorder or psychotic depression should prompt a neurological assessment to rule out multiple sclerosis. The workup should include careful physical examination, examination of the cerebrospinal fluid, CT scan, MRI scanning if available and sensory evoked potentials (31,32). As already discussed, the error of attributing early signs of MS to lithium or
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MS AND MOOD DISORDERS
neuroleptic toxicity, histronic somatization or conversion disorder is well documented in the literature (27,28,30). In view of the well known geographic variation in the incidence of multiple sclerosis (33), the psychiatrist should be most suspicious in cases from high-risk areas. Acknowledgement The authors are grateful to Joanne Steven for technical assistance in preparing the manuscript.
References I. Cottrell SS, Wilson SA. Affective symptomatology of disseminated sclerosis. J Neurol Psychopathol 1926; 7: 1-30. 2. Sugar C, Nadell R. Mental symptoms in multiple sclerosis. J Nerv Ment Dis 1943; 98: 267-280. 3. Whitlock FA, Siskind MM. Depression as a major symptom of multiple sclerosis. J Neurol Neurosurg Psychiatry 1980; 43: 861-86.5. 4. Schiffer RB, Wineman NM, Weitkamp LR. Association between bipolar affective disorder and multiple sclerosis. Am J Psychiatry 1986; 143: 94-95. 5. Cass U, Alexander L, Enders M. Complications of corticotrophin therapy in multiple sclerosis. JAMA 1966; 197: 173-178. 6. Glaser GH. Psychotic' reactions induced by corticotrophin (ACTH) and cortisone. Pychosom Med 1953; 15: 280-291. 7. Kemp K, Lion JR, Magram G. Lithium in the treatment of a manic patient with multiple sclerosis: a case report. Dis Nerv Syst 1977; 38: 210-211. 8. Falk WE, Mahnke MW, Poskanzer DC. Lithium prophylaxis of corticotropin-induced psychosis. JAMA 1979; 241: 1011-1012. 9. Diagnostic and statistical manual of mental disorders, third edition. revised. Washington DC: American Psychiatric Press, Inc., 1987. 10. Pratt RTC. An investigation of the psychiatric aspects of disseminated sclerosis. J Neurol Neurosurg Psychiatry 1951; 14: 326-335. 11. Baldwin MV. A clinico-experimental investigation into the psychological aspects of multiple sclerosis. J Nerv Ment Dis 1952; 115:299-342. 12. Surridge D. An investigation into some psychiatric aspects of multiple sclerosis. Br J Psychiatry 1969; 115: 749-764. 13. Mcivor GP, Riklan M, Reznikoff M. Depression in multiple sclerosis as a function of length and severity of illness, age, remissions, and perceived social support. J Clin Psychol 1984; 40: 1028-1033. 14. Baretz RM, Stephenson GR. Emotional responses to multiple sclerosis. Psychosomatics 1981; 22: 117-127. 15. Dalos NP, Rabins PV, Brooks BR, et al. Disease activity and emotional state in multiple sclerosis. Ann Neurol 1983; 13: 573-577. 16. Rabins PV, Brooks BR, O'Donnell P, et al. Structural brain correlates of emotional disorder in multiple sclerosis. Brain 1986; 109: 585-597. 17. Gallineck A, Kalinowsky L. Psychiatric aspects of multiple sclerosis. Dis Nerv Syst 1958; 19: 77-80. 18. Goodstein RK, Ferrell RB. Multiple sclerosis - presenting as depressive illness. Dis Nerv Syst 1977; 38: 127-131. 19. Schiffer RB,Caine ED, Bamford KA, et al. Depressive episodes in patients with multiple sclerosis. Am J Psychiatry 1983; 140: 1498-1500.
20. Joffe RT,Lippert GP,GrayTA, et al. Personal and family history of affective illness in patients with multiple sclerosis. J Affective Disord 1987; 12: 63-65. 21. Schiffer RB. The spectrum of depression in multiple sclerosis. Arch Neuro11987; 44: 596-599. 22. Kathol RG, Petty F. Relationship of depression to medical illness. A critical review. J Affective Disord 1981; 3: 111-121. 23. Ross ED, Rush J. Diagnosis and neuroanatomical correlates of depression in brain-damaged patients. Arch Gen Psychiatry 1981; 38: 1344-1354. 24. Honer WG, Hurwitz T, Li DKB, et al. Temporal lobe involvement in multiple sclerosis patients with psychiatric disorders: a magnetic resonance imaging study. Arch Neurol 1987; 44: 187-190. 25. Krauthammer C, Klerman GL. Secondary mania. Manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry 1978; 35: 1333-1339. 26. Cremieux A, AlliezJ, Toga M, et al. Sclerose en plaques a debut par troubles mentaux: etude anatomoclinique. Revue Neurologique (Paris) 1959; 101: 45-51. 27. Peselow ED, Deutsch SI, Fieve RR, et al. Coexistent manic symptoms and multiple sclerosis. Psychosomatics 1981; 22: 824-825. 28. Solomon JG. Multiple sclerosis masquerading as lithium toxicity. J Nerv Ment Dis 1978; 166: 663-665. 29. Mapelli G, Ramelli E. Manic symptoms associated with multiple sclerosis: secondary mania? Acta Psychiatr Belg 1981; 81: 337-349. 30. Kellner CH, Davenport Y, Post RM, et al. Rapidly cycling bipolar disorder and multiple sclerosis. Am J Psychiatry 1984; 141: 112-113. 31. Salloway S, Price LH, Charney DS, et al. Multiple sclerosis presenting as major depression: a diagnosis suggested by MRI scan but not CT scan. J Clin Psychiatry 1988; 49: 364-366. 32. Farlow MR, Markand ON, Edwards MK, et al. Multiple sclerosis: magnetic resonance imaging, evoked responses, and spinal fluid electrophoresis. Neurology 1986; 36: 828-831. 33. Baum HM, Rothschild BB. The incidence and prevalence of reported multiple sclerosis. Ann Neurol 1981; 10: 420-428.
Resume On attribue les troubles affectifs lies a la sclerose en plaques ii la fois aux effets psychologiques d' une maladie inv ali dant e et aux lesions structure lies dues ii la demyelinisation du cerveau. Une revue des resultats de recherche donne ii penser que, alors que les symptomes de depression chronique sont en correlation avec l'invalidite progressive et Ie manque de soutien social,les grandes crises algues de depression et de manie sont peut-etre la manifestation psychique de Lesions demyelinisantes et les premiers signes apparents de la maladie. Le traitement des symptomes psychiques aigus exige parfois la prescription d' anti-inflammatoires, meme si ces substances tendent a precipiter les crises psychotiques. On presente deux cas qui illustrent la difficulte de distinguer cliniquement la maladie organique des troubles affectifs fonctionnels chez Ie malade atteint de sclerose en plaques.
M.D. 1 AND
AP.
ZIS, M.D. 2
psychotic reactions remains speculative, the occurrence of a mood disturbance as a complication of anti-inflammatory therapy is so frequent that prophylactic lithium therapy has been recommended for MS patients receiving ACTH (8). The widely used diagnostic classification system, DSM-III-R (9), specifies that major affective disorders and organic affective disorder are mutually exclusive diagnoses. The diagnosis of organic affective disorder would lead to the treatment of the underlying organic cause as the primary treatment of affective symptoms. On the other hand, the diagnosis of acute affective symptoms of a functional nature might lead to deliberate avoidance of specific anti-inflammatory agents which may precipitate psychiatric symptoms. This dilemma has received little attention in the psychiatric literature. Authors discussing affective symptoms in the presence of MS have tended to favour either an organic or functional causation. Yet the clinician is frequently confronted with complex multifactorial causation and with the problem of recommending optimal treatment. The purpose of this report is to review the evidence of an association between MS and depressive symptoms, major depressive disorder and bipolar disorder with a particular emphasis on the various factors which may account for this association. Two case reports are included to illustrate the complex interplay of biological and psychosocial factors in the genesis of major affective disorders in patients with MS.
Affective disorders occurring in association with multiple sclerosis have been attributed both to the psychosocial impact of a chronic disabling illness and to the structural lesions of cerebral demyelination. A review of research evidence suggests that while there is a correlation between chronic depressive symptoms and both progressive disability and lack of social support, acute major depressive and manic episodes may be psychiatric manifestations of demyelinating lesions and may be the initial presenting symptoms of multiple sclerosis. Anti-inflammatory agents may be required in the management of acute psychiatric symptoms despite the fact that these agents have a propensity to precipitate psychotic episodes. Two case reports are presented to illustrate the clinical challenge of distinguishing between organic and functional affective illness in patients with multiple sclerosis. The interplay between biological and psychological aspects of multiple sclerosis in precipitating affective disorders is discussed, with implications for patient assessment and management.
C
hanges in prevailing mood and emotional control have been recognized as being characteristic of multiple sclerosis (MS) since the publication of landmark reports earlier this century (1,2). However, the association between MS and specific mood disorders, including major depressive episodes (3) and bipolar affective disorder (4), has only recently been documented. There are several hypothetical explanations for this observed association. First, MS could act as a psychological stressor precipitating depression or mania in a psychologically and/or biologically predisposed individual. Second, MS produces specific structural lesions which may cause affective disorders. Third, susceptibilities to MS and to affective disorders may be genetically linked. A confounding factor in this field is the fact that drugs used in the treatment of MS are known to produce mood changes. Corticotrophin (ACTH) and corticosteroids may precipitate manic or depressive psychotic episodes in patients treated for inflammatory disorders (5-7). While the mechanism of these
Depression and Multiple Sclerosis When examining the relationship between depression and MS, it is important to distinguish between depressed mood and major depressive episodes. Systematic documentation of the occurrence of major depressive episodes has occurred only in recent surveys. Earlier reports of depressive symptomatology are summarized in Table I. Notable in the earliest studies of clinical populations (1,2) are the frequent reports of affective instability (86% to 97%) suggestive of organic disinhibition, compared with the low rates of self-reported depressive symptoms (ten percent to 17.5%). Subsequent studies have documented more selfreported depressive symptoms in patients with MS than in neurological controls (10) or healthy controls (II). This relationship holds even when depression inventory items potentially reflecting MS symptoms are eliminated (II). Several studies indicate that there is a correlation between depressive symptoms in MS patients and both progressive disability and lack of social support, and that they are no more frequent than in neurological controls with non cerebral disorders matched for disability (11-15). It has been concluded,
*Manuscript received August 1989; revised December 1989. I Clinical Instructor, Department of Psychiatry, University of British Columbia, University Hospital- UBC Site.Vancouver, British Columbia. 2Professor, Department of Psychiatry.University of British Columbia. University Hospital- UBC Site, Vancouver. British Columbia. Address reprints requests to: EJ. Garland. M.D .• 2211 Wesbrook Mall. Vancouver BC V6T 2B5
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Table I Surveys of Depressive Symptoms in Patients with Multiple Sclerosis N
Controls
DepressiveSymptoms
Comments
Cottrell (I)
100
10% pessimistic
97% loss·of emotional control
Sugar (2)
28
17.5%dysphoric
86% loss of emotional control
Pratt (10)
100
100
29% "cry easily" versus 17%of controls
significantdifference; neurological controls
Baldwin (II)
85
85
MMPI: significantincrease in depression hypochondriasis and hysteria scales in MS
healthy controls; scale items reflecting MS symptoms eliminated
Surridge (12)
100
39
27% of MS patients depressed in psychiatricinterviewversus 13%of controls (not statistically significant)
matchedfor disability
McIvor (13)
120
Beck Depression Inventory scores elevated
correlationbetween symptoms and disability and lack of support
therefore, that these depressive symptoms are "reactive". However, Rabins et al (16) reported that depression scores were higher in MS patients with more clinically diagnosed brain involvement, suggesting a role for "organic" factors. Studies of major depressive episodes in MS patients are summarized in Table II. These studies were preceded by several case reports (17,18). Gallinek and Kalinowsky (17) reported three cases which were judged to be "reactive" in nature, including two cases that responded to ECT. Goodstein and Ferrell (18) reported three cases in which single or multiple depressive episodes preceding neurological symptoms were viewed in retrospect as the first manifestations of MS. It is notable, however, that the neurological symptoms had been initially viewed as "psychogenic" in these cases. Whitlock and Siskind (3), in the first systematic study of depressive episodes in MS patients, found a higher incidence of major depressive episodes in MS patients after the onset of MS than in neurological controls matched for disability. In two patients, depressive episodes occurring prior to MS diagnosis were believed to represent demyelinat-
ing episodes. Scores on the Beck Depression Inventory (BDI) were higher in MS patients, especially those whose disability was more severe. Whitlock and Siskind's data support Goodstein and Ferrell's hypothesis that there is a true association between major affective disorders and MS; MS lesions cause symptoms rather than precipitating major depressive episodes through psychological mechanisms. Consistent with earlier surveys (11-14), however, this report also suggests that progressive disability may predispose patients with MS to developing chronic depressive symptoms. While family histories of affective disorder were not reported, it was noted that MS patients did not receive more drugs that are likely to produce depressive symptoms than did controls. Schiffer (19) examined the role of structural lesions in producing depressive symptoms by comparing cerebral MS with noncerebral MS patients matched on the Kurtzke Disability Scale, finding a higher incidence of major depressive episodes in patients with cerebral MS. These results suggest that structural damage is involved in the genesis of major depression. The observation that a similar degree of cognitive
Table II Reports of Major Depressive Episodes in Patients with Multiple Sclerosis Subjects
Incidenceof Major Depression
Whitlock (3)
30 with MS; 30 neurologicalcontrols matched for disability
16of the MS cases; 5 of the controls
significantdifference; BOI scores higher in MS cases; MS onset with depression in 2 cases
Schiffer (4)
15 with cerebral MS; 15 with noncerebral MS
9 of the cerebral MS cases; 2 of the non cerebral MS cases
significantdifference; matched for disability; BOI scores not different
Joffe (20)
100consecutive patients at an MS clinic
55 met the SADS-Lcriteria for major affective disorder: 42 with major depression; 13 with bipolar affective disorder
family incidenceof affective disorder not elevated
Comments
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impairment occurred in both groups suggests that the depressive symptoms were the result of specific lesions rather than reflecting a generalized decrease in cognitive functioning, which might impair coping strategies. The question of whether or not susceptibilities to MS and to depressive disorder are genetically linked has received little attention in these reports. However, Joffe et al (20) recently reported a 42% lifetime occurrence of major depressive episodes in MS clinic patients. The incidence of family histories of affective illness was not higher than in the general population, data which argue strongly against this hypothesis. Response to specific treatment may provide circumstantial evidence of a particular etiological factor. Schiffer (21) has recently reported the results of a management protocol in which 20 MS patients with a major depressive episode were assigned to medical, psychological or social treatment according to the presumed major etiological precipitant. Regardless of treatment strategy, depressive episodes were resolved within five weeks in 12 of the 13 patients with relapsing or progressive MS. In contrast, seven of eight patients who developed depressive episodes during remission remained depressed regardless of treatment. These results could be consistent with the etiological role of either organic or psychosocial factors. The available evidence to date suggests that there is a con-elation between the presence of depressive symptoms in MS patients and disability and lack of social support, which may not be unique to MS, while major depressive episodes may be the result of the structural lesions of MS. Factors limiting the interpretation of these data include the well known impact of symptoms of medical illness on depression scales (22), the lack of information on genetic predisposition to developing an affective disorder in some study populations, and the lack of data on the localization of MS structural lesions which might provide a pattern correlating with affective illness (23). The availability of magnetic resonance imaging (MRI) to assist in localizing MS lesions may enhance our understanding of this field. Arecent MRI study of patients suffering from MS found a greater degree of temporal lobe involvement in eight MS patients with psychiatric disorders than in MS controls matched for age, sex, duration, severity and course of illness (24). Bipolar Affective Disorders and Multiple Sclerosis Early investigators of psychological changes in MS reported a high incidence of euphoria and "eutonia", or abnormal sense of bodily well-being. Euphoria was noted in 63% of Cottrell and Wilson's study population (1) and 54% of Sugar and Nadell's (2). While these early reports suggested a low incidence of intellectual deterioration, Surridge (12) demonstrated intellectual deficits in 60%, hyponosognosia in 31 %, and a relationship between cognitive impairment and euphoria, which has been confirmed in a recent report (14). Abnormal mood elevation may also be associated with concealed depression (13,14). However, hypomanic episodes were not noted in these reports. In a landmark paper review-
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ing the concept of organically caused "secondary mania" (25), mention of MS as a cause is conspicuously absent. In a recent epidemiological study, Schiffer (4) demonstrated a greater than expected statistical association between bipolar affective disorder and MS in Monroe County, USA. In the ten cases identified, the affective disorder began after the onset of the neurological symptoms. A family history of affective illness was present in half of these cases. Joffe et al (20) subsequently reported a lifetime occurrence of bipolar disorder in 13 of 100 consecutive MS clinic patients. There was no difference between the incidence of a family history of affective disorder in MS patients and that in the general population. While a true association is suggested and there is no evidence to support genetic linkage, the data provided do not indicate whether MS was a psychological stressor or a direct organic cause, or whether affective illness occurred during treatment of MS with agents known to cause psychiatric symptoms. . Table III summarizes case reports of mania and cyclical mood disturbances in association with MS. Although these are anecdotal, several important observations appear in these reports: acute mania may be a clinical presentation of MS (26-29); neurological signs of MS may be misdiagnosed as lithium or neuroleptic toxicity (27,28) or "dismissed" as psychogenic (30); and treatment of manic symptoms in these patients may require anti-inflammatory agents (27,29). All of these authors have suggested that the mood disorder is a manifestation of the demyelinating disorder. While in some cases the mood disorder is a clinical manifestation of acute demyelination, in other reported cases the structural damage of MS plaques is reflected in a chronic, treatment-resistant cyclical mood disturbance (30). Bipolar mood disorder occurs in association with multiple sclerosis at a rate greater than that predicted by chance and in the absence of a predisposing family history. This appears to be an organic mood disorder. Case Reports Case 1 A 32 year old married professional woman with two young children presented with a major depressive episode with mood congruent and incongruent psychotic features. The symptoms had developed insidiously during the six months after the acute onset of multiple sclerosis. The diagnosis of MS had been confirmed by compterized tomography (CT) scan, magnetic resonance imaging (MRI), and cerebrospinal fluid changes. Since her initial presentation with diploplia, dysarthria, left-sided weakness and paresthesia after a flu-like illness, she had experienced several exacerbations of neurological symptoms and was unable to return to work. She reported progressive fatigue, social withdrawal, depressed mood, apathy, anhedonia, indecisiveness and ruminations of guilt. She developed initial insomnia and early morning wakening, anorexia with a 5 kg weight loss and passive suicidal ideation. She had paranoid delusions that her husband was planning to divorce her and that she was being covertly observed by detectives, family members and
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Table III Case Reports of Bipolar Affective Disorder and Multiple Sclerosis Age
Case
Sex
Order of Symptom Presentation
Comments
Cremieux (26)
'47
M
mania followed by neurological symptoms5 monthslater; cyclical manic depressiveillnessand progressive neurological symptoms, fatal 2 years later
autopsy findings includedtemporal lobe, thalamic and periventricular lesions
Peselow(27)
29
M
neurological symptoms simultaneously with mania which was unremitting for 8 months
neurological symptoms initiallymisdiagnosed as neuroleptic and lithium toxicity; mania unremitting until prednisonetherapy instituted
Solomon (28)
58
M
mania followed 6 months later by neurological symptoms
neurological symptoms misdiagnosed as lithium toxicity
Mapelli (29)
26
F
transientneurological symptomsfollowed 3 years laterby mania; neurological symptomssimultaneous with second manic episode
second manic episode required treatment with ACTH and neuroleptics
Kellner (30)
29
F
rapid cycling mood disorderfor 3 years followed by neurolgical symptoms
history of "conversionreaction" 4 years prior to onset of mood disorder
Kellner (30)
53
F
rapid cycling mood disorder for 3 years followed by neurological symptoms
neurological symptomsmisdiagnosed as alcoholic'cerebellar ataxia
therapists. She reported hallucinatory voices commenting on her behaviour and mocking her for her failures. There were also several episodes of formed visual hallucinations of animals. On psychiatric admission, the patient presented with marked psychomotor retardation, profoundly depressed mood, flattened affect, delusions of a paranoid type, and hallucinatory voices making derogatory comments. Physical examination revealed a resting tremor in the left leg, bilateral optic atrophy, hyperreflexia and left extensor plantar response. While she had no prior history of psychiatric illness, her personal history suggested a biological and psychological predisposition to depression. The patient's mother had received ECT for two major depressive episodes. As a child, the patient was introverted and isolated. Her father deserted the family when she was four. Her first serious relationship was with her husband and was characterized by insecurity, which she attributed to this early loss. Precipitating factors for depression occurred in the several years prior to the onset of MS. After years of marriage, she became pregnant. Ambivalent about both parenthood and abortion, her husband left the decision to her. She then felt guilty and anxious when the birth of twins severely strained the marriage. The onset of MS left her with a sense of personal, occupational and marital failure. Furthermore, because she believed in the metaphysical causation of illness, she blamed herself for unconsciously creating the illness to escape her many responsibilities.
Neurological assessment on her psychiatric admission did not reveal clinical evidence of acute demyelination. The daily administration of nortriptyline 75 mg and haloperidol 6 mg resolved her depression and delusions within four weeks. Individual and marital supportive psychotherapy was directed at helping the patient and her husband grieve appropriately for her diagnosis of MS, which they had not yet accepted. After resolution of the major depressive episode, clinical assessment suggested cognitive deficits manifesting as concrete thinking and problem solving inconsistent with the patient's educational level. Neuropsychological testing confirmed impaired problem solving, vulnerability to distraction, ideomotor apraxia and a 3 I point verbal-performance spread on the WAIS-R. A schizotypal personality pattern appeared on the MCMI. Repeat MRI scanning revealed new lesions since the examination three months previously. This suggests, in retrospect, that neurologically silent lesions may have contributed to the psychiatric disorder. Although the preferred diagnosis was a functional major depressive episode with psychotic features, clearly organic affective disorder could not be excluded.
ease 2 The patient was a 30 year old unemployed labourer who presented with acute mania and neurological deterioration followed by a depressive episode six months later. Seven years previously, the patient developed spontaneously resolving paresthesia of the left arm. When symptoms recurred two years later, multiple sclerosis was
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diagnosed, and the illness foIlowed a chronic relapsing and remitting course. During one episode several grand mal seizures occurred, and prednisone was administered without reported adverse effects. The first psychiatric admission was for acute mania accompanied by new symptoms of ataxia, dysarthria and paresthesia. There was a one week history of sleeplessness, overactivity, overspending, overtalkativeness with flight of ideas, grandiose delusions and extreme irritability. Because of the temporal association with neurological deterioration and the findings of new bifrontallesions using MRI, a diagnosis of organic affective disorder was made. The patient was treated with chlorpromazine and plasmapheresis followed by a cyclophosphamide trial, and his symptoms were resolved over several weeks. A history of depressive symptoms occurring three months previously was elicited at that time. Six months later the patient was readmitted with suicidal ideation. There was a six week history of depressed mood, insomnia with early waking, anorexia, decreased libido, poor concentration, apathy, anhedonia and ruminations of guilt that his illness was a punishment for his past antisocial behaviour. Three weeks prior to this admission, the neurologist had prescribed prednisone 60 mg daily because of increasing ataxia. The patient reported that his mood disturbance worsened after this was initiated, although his neurological symptoms improved. A mental status examination revealed depressed mood and affect, psychomotor retardation, ruminations of guilt, suicidal ideation, impaired concentration and markedly concrete interpretation of proverbs. Physical examination demonstrated ataxia, bilateral hyperreflexia, extensor plantar responses, dysdiadochokinesia and intention tremor on the left side. MRI scanning demonstrated numerous cerebral and cerebellar lesions including a prominent right temporal lobe lesion, but there were no new findings with the exception of progressive ventricular dilatation. The neurological assessment revealed that there was no evidence of active demyelination, and prednisone was tapered as planned. Imipramine was initiated at a dose of 50 mg daily. Within a week, the patient's mood, energy, concentration and psychomotor activity had dramatically recovered. He had no suicidal ideation and had realistic plans to enter a retraining program. He chose to discontinue imipramine therapy on discharge, and it was considered unlikely that this brief low dose antidepressant treatment had contributed substantially to his improvement. The working diagnosis at this point was organic bipolar affective disorder. Prednisone therapy was presumed to have contributed to depressive symptoms. It was noted that the patient's personal history suggested a biological, psychological and social predisposition to affective illness. There was a history of depression, alcohol abuse and violent suicide in his father and paternal uncle, and "mood swings" in a brother. The father left the family when the patient was seven years old and committed suicide when the patient was 14. The fifth of ten siblings, the patient had
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avoidant traits and developed antisocial behaviour patterns beginning in the year after his father's death, including minor criminal offenses, alcohol and recreational drug abuse. After failing to complete high school despite apparent ability, he drifted across the country working at odd jobs. He had repeated difficulty with employers and became estranged from his family. After his MS symptoms appeared, he was less able to perform physical labour, and employment became irregular. He became socially isolated and increasingly dependent on his live-in girlfriend for physical and financial support. He expressed chronic feelings of discouragement, self-blame and low self-esteem, which he continued to experience after his major depressive episode had been resolved. Discussion . The two cases presented demonstrate the complex interplay between biological and psychosocial factors in the genesis of affective illness in association with multiple sclerosis. These patients were genetically predisposed to affective disorders, and psychological predisposition was evident in both developmental histories. In each case there was an early loss of a parent and evidence of the psychological impact of this loss. For both of these patients, MS became one of a number of stressors which could precipitate an affective illness. Furthermore, there was evidence in each case to suggest that the structural lesions of MS contributed to the psychiatric illness. Recognition of the complex pathogenesis of affective illness in association with MS has several important practical implications. First, an acute affective disorder in a patient with MS should lead to careful neurological assessment to determine whether or not this could be a manifestation of acute demyelination. Computerized tomography or magnetic resonance imaging may be required to detect neurologically silent but psychiatrically manifested demyelination. Anti-inflammatory agents may therefore be specifically indicated in the presence of acute psychiatric symptoms, but coverage with lithium, neuroleptics or antidepressants is suggested. Second, even in a patient with an organic affective syndrome, psychodynamic and psychosocial factors need to be ascertained and addressed in order to reduce chronic depressive symptoms of a reactive nature. It can also be predicted that the individual with a structural lesion producing acute affective symptoms may be more prone to future episodes of an affective disorder, to which psychological stressors may contribute. Finally, the occurrence of transient, unexplained neurological disturbances in a patient with bipolar affective disorder or psychotic depression should prompt a neurological assessment to rule out multiple sclerosis. The workup should include careful physical examination, examination of the cerebrospinal fluid, CT scan, MRI scanning if available and sensory evoked potentials (31,32). As already discussed, the error of attributing early signs of MS to lithium or
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neuroleptic toxicity, histronic somatization or conversion disorder is well documented in the literature (27,28,30). In view of the well known geographic variation in the incidence of multiple sclerosis (33), the psychiatrist should be most suspicious in cases from high-risk areas. Acknowledgement The authors are grateful to Joanne Steven for technical assistance in preparing the manuscript.
References I. Cottrell SS, Wilson SA. Affective symptomatology of disseminated sclerosis. J Neurol Psychopathol 1926; 7: 1-30. 2. Sugar C, Nadell R. Mental symptoms in multiple sclerosis. J Nerv Ment Dis 1943; 98: 267-280. 3. Whitlock FA, Siskind MM. Depression as a major symptom of multiple sclerosis. J Neurol Neurosurg Psychiatry 1980; 43: 861-86.5. 4. Schiffer RB, Wineman NM, Weitkamp LR. Association between bipolar affective disorder and multiple sclerosis. Am J Psychiatry 1986; 143: 94-95. 5. Cass U, Alexander L, Enders M. Complications of corticotrophin therapy in multiple sclerosis. JAMA 1966; 197: 173-178. 6. Glaser GH. Psychotic' reactions induced by corticotrophin (ACTH) and cortisone. Pychosom Med 1953; 15: 280-291. 7. Kemp K, Lion JR, Magram G. Lithium in the treatment of a manic patient with multiple sclerosis: a case report. Dis Nerv Syst 1977; 38: 210-211. 8. Falk WE, Mahnke MW, Poskanzer DC. Lithium prophylaxis of corticotropin-induced psychosis. JAMA 1979; 241: 1011-1012. 9. Diagnostic and statistical manual of mental disorders, third edition. revised. Washington DC: American Psychiatric Press, Inc., 1987. 10. Pratt RTC. An investigation of the psychiatric aspects of disseminated sclerosis. J Neurol Neurosurg Psychiatry 1951; 14: 326-335. 11. Baldwin MV. A clinico-experimental investigation into the psychological aspects of multiple sclerosis. J Nerv Ment Dis 1952; 115:299-342. 12. Surridge D. An investigation into some psychiatric aspects of multiple sclerosis. Br J Psychiatry 1969; 115: 749-764. 13. Mcivor GP, Riklan M, Reznikoff M. Depression in multiple sclerosis as a function of length and severity of illness, age, remissions, and perceived social support. J Clin Psychol 1984; 40: 1028-1033. 14. Baretz RM, Stephenson GR. Emotional responses to multiple sclerosis. Psychosomatics 1981; 22: 117-127. 15. Dalos NP, Rabins PV, Brooks BR, et al. Disease activity and emotional state in multiple sclerosis. Ann Neurol 1983; 13: 573-577. 16. Rabins PV, Brooks BR, O'Donnell P, et al. Structural brain correlates of emotional disorder in multiple sclerosis. Brain 1986; 109: 585-597. 17. Gallineck A, Kalinowsky L. Psychiatric aspects of multiple sclerosis. Dis Nerv Syst 1958; 19: 77-80. 18. Goodstein RK, Ferrell RB. Multiple sclerosis - presenting as depressive illness. Dis Nerv Syst 1977; 38: 127-131. 19. Schiffer RB,Caine ED, Bamford KA, et al. Depressive episodes in patients with multiple sclerosis. Am J Psychiatry 1983; 140: 1498-1500.
20. Joffe RT,Lippert GP,GrayTA, et al. Personal and family history of affective illness in patients with multiple sclerosis. J Affective Disord 1987; 12: 63-65. 21. Schiffer RB. The spectrum of depression in multiple sclerosis. Arch Neuro11987; 44: 596-599. 22. Kathol RG, Petty F. Relationship of depression to medical illness. A critical review. J Affective Disord 1981; 3: 111-121. 23. Ross ED, Rush J. Diagnosis and neuroanatomical correlates of depression in brain-damaged patients. Arch Gen Psychiatry 1981; 38: 1344-1354. 24. Honer WG, Hurwitz T, Li DKB, et al. Temporal lobe involvement in multiple sclerosis patients with psychiatric disorders: a magnetic resonance imaging study. Arch Neurol 1987; 44: 187-190. 25. Krauthammer C, Klerman GL. Secondary mania. Manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry 1978; 35: 1333-1339. 26. Cremieux A, AlliezJ, Toga M, et al. Sclerose en plaques a debut par troubles mentaux: etude anatomoclinique. Revue Neurologique (Paris) 1959; 101: 45-51. 27. Peselow ED, Deutsch SI, Fieve RR, et al. Coexistent manic symptoms and multiple sclerosis. Psychosomatics 1981; 22: 824-825. 28. Solomon JG. Multiple sclerosis masquerading as lithium toxicity. J Nerv Ment Dis 1978; 166: 663-665. 29. Mapelli G, Ramelli E. Manic symptoms associated with multiple sclerosis: secondary mania? Acta Psychiatr Belg 1981; 81: 337-349. 30. Kellner CH, Davenport Y, Post RM, et al. Rapidly cycling bipolar disorder and multiple sclerosis. Am J Psychiatry 1984; 141: 112-113. 31. Salloway S, Price LH, Charney DS, et al. Multiple sclerosis presenting as major depression: a diagnosis suggested by MRI scan but not CT scan. J Clin Psychiatry 1988; 49: 364-366. 32. Farlow MR, Markand ON, Edwards MK, et al. Multiple sclerosis: magnetic resonance imaging, evoked responses, and spinal fluid electrophoresis. Neurology 1986; 36: 828-831. 33. Baum HM, Rothschild BB. The incidence and prevalence of reported multiple sclerosis. Ann Neurol 1981; 10: 420-428.
Resume On attribue les troubles affectifs lies a la sclerose en plaques ii la fois aux effets psychologiques d' une maladie inv ali dant e et aux lesions structure lies dues ii la demyelinisation du cerveau. Une revue des resultats de recherche donne ii penser que, alors que les symptomes de depression chronique sont en correlation avec l'invalidite progressive et Ie manque de soutien social,les grandes crises algues de depression et de manie sont peut-etre la manifestation psychique de Lesions demyelinisantes et les premiers signes apparents de la maladie. Le traitement des symptomes psychiques aigus exige parfois la prescription d' anti-inflammatoires, meme si ces substances tendent a precipiter les crises psychotiques. On presente deux cas qui illustrent la difficulte de distinguer cliniquement la maladie organique des troubles affectifs fonctionnels chez Ie malade atteint de sclerose en plaques.
